Mechanisms of lincDUSP Oncogenic Effects in Colon Cancer

派：哈利勒，艾哈迈德 技术摘要： 结肠癌是美国癌症相关死亡的第二大原因，在很大程度上 由于治疗失败和复发频繁。最近的研究，包括我们的工作 实验室已经证明，受调控的长基因间非编码RNA(LincRNAs)是 在结肠肿瘤发生过程中的主要参与者，并可能成为新的治疗方法 目标。在本方案中，我们鉴定了一种新的lincRNA并对其进行了功能鉴定， 被称为lincDUSP，在结肠癌细胞中发挥致癌作用。击倒 LincDUSP显著消除肿瘤表型，包括抑制增殖和 集落形成，细胞凋亡率增加。这些研究还表明，lincDUSP 通过直接与染色质相互作用调节大量基因，并潜在地招募 蛋白质复合体到特定的基因组位置。在这项建议的目标1中，我们将进一步测试 利用异种移植模型研究lincDUSP在体内的致癌作用，并评估其作用。 LincDUSP在使用3D有机化合物推动结肠肿瘤发生中的作用。在目标2中，我们将调查 通过评估lincDUSP在基因调控中的作用来探讨其分子机制，并对其进行了表征 LincDUSP致癌活性所需的蛋白质复合体。最后，我们将 确定促进其与DNA相互作用的lincDUSP的二级结构 蛋白质。拟议研究的完成可能导致将lincDUSP作为一种小说 致癌lincRNA对结肠癌的发生有直接影响，并可能成为 心理治疗。

PI: Khalil, Ahmad Technical Abstract: Colon cancer is the second leading cause of cancer-related death in the United States, largely due to frequent treatment failure and recurrence. Recent studies, including work from our laboratory, have demonstrated that regulatory long intergenic non-coding RNAs (lincRNAs) are major players in the process of colon tumorigenesis, and could emerge as novel therapeutic targets. In this proposal, we have identified and functionally characterized a novel lincRNA, referred to as lincDUSP, that exerts an oncogenic effect in colon cancer cells. Knockdown of lincDUSP significantly abrogates the tumor phenotype, including decreased proliferation and colony formation, and increased apoptosis. These studies have also revealed that lincDUSP regulates numerous genes by directly interacting with chromatin, and potentially recruiting protein complexes to specific genomic loci. In aim 1 of this proposal, we will further test the oncogenic function of lincDUSP in vivo using a xenograft model, and also assess the role of lincDUSP in driving colon tumorigenesis using 3D organoids. In aim 2, we will investigate the molecular mechanisms of lincDUSP by assessing its role in gene regulation, and characterize the protein complexes that are required for lincDUSP oncogenic activity. Lastly, we will determine the secondary structure of lincDUSP that facilitates its interaction with DNA and proteins. The completion of the proposed studies could lead to establishing lincDUSP as a novel oncogenic lincRNA with direct impact on colon tumorigenesis, and possibly as a target for therapy.